In hepatocellular carcinoma (HCC) management, the Child-Pugh (CP) score is the current standard tool for assessing the underlying chronic liver disease (CLD) status in clinical practice and stratifying patients in HCC therapeutic trials. It alo is an essential parameter in most currently used HCC staging systems, particularly Cancer of the Liver Italian Program (CLIP) and Barcelona Clinic Liver Cancer (BCLC). Multiple experts panels consensus statements reached the consensus that patients with HCC considered for surgical resection or local or systemic therapeutic trials must have a CP score of A [1-3]. This selection criterion facilitates assessment of the effect of treatment without the confounding issues of liver failure and death as a result of underlying cirrhosis. However, the panels also acknowledged the need to refine the CP score since it is relatively quantitative. The score uses five variables: three objective laboratory-based parameters that assess the synthetic function of the liver through serum albumin level and prothrombin time or the elimination function of the liver through measuring serum bilirubin level, in addition to two subjective clinical parameters, hepatic encephalopathy and ascites. The last two parameters are clinically difficult to grade, may be precipitated by other nonliver diseases, and may vary in severity according to treatment with diuretics and lactulose. Thus, major refinement of the CP score is critically needed to optimize HCC management and improve the typically dismal outcome of this disease. Our most recent published reports described the use of the plasma insulin-like growth factor (IGF)-1 level as a tool for assessing the status of the underlying CLD. Integration of measurement of this level into the CLIP and BCLC systems significantly improved their predictive ability and refined HCC patient stratification. Therefore, our overall goal for the proposed study is to develop a noninvasive biomarker-based strategy to personalize HCC classification. Our central hypothesis is that the baseline plasma IGF-1 level is an easily measured surrogate prognostic biomarker of the extent of hepatic dysfunction that can be used instead of assessment of ascites and hepatic encephalopathy to refine the predictive ability of CP and HCC classifications. We will test this hypothesis in three specific aims: 1) To construct a new CP score and new CLIP and BCLC staging systems by integrating plasma IGF-1 measurement into the CP score parameters. 2) To compare the performance of the original CP score and CLIP and BCLC staging systems with that of the IGF-integrated systems. 3) To prospectively validate the performance of the IGF-1-integrated CP score and CLIP and BCLC staging systems in an independent cohort of HCC patients. Should we achieve our aims we may be able to develop new strategies in personalized therapy in better designed clinical trials of comparable criteria. PUBLIC HEALTH RELEVANCE: Our most recently published studies indicated the potential use of measurement of plasma insulin-like growth factor-1 levels as a tool to assess the status of underlying liver disease in patients with hepatocellular carcinoma (HCC). The goal of our proposed study is to construct and validate insulin-like growth factor-1-integrated HCC classification systems. This approach to classification of HCC may lead to personalized therapeutic strategies and allocation of health care resources and will aid researchers in designing clinical trials of comparable criteria.